The focus of this project is to delineate JC virus (JCV) genotypes circulating in humans, with special emphasis on the biological effects of African genotypes. In addition, the neuropathology of progressive multifocal leukoencephalopathy (PML) will be studied with a view to determine genotype-specific differences in the clinical presentation and natural history of PML. JCV is a member of the genus polyomavirinae which includes Simian virus 40 (SV 40) and KB virus (BKV). Worldwide seroepidemiologic studies on JCV have shown a 70% prevalence in humans, while approximately 40% of adults excrete this virus in urine. Sequence analysis of JCV Dana has revealed several geographically based genotypes, the most common of which are: Type 1 (European); Type 2 (Asian); Types 3 and 6 (African); and Type 4 (USA). JCV causes PML, a chronic demyelinating disease of the central nervous system. Prior to AIDS, PML was rarely found except ion immunocompromised patients with hematologic malignancies. Reported incidence has since increased, occurring in 0.8% (Brazilian), 1.5 % (African), 4-5% (USA), and 7-10% (European) AIDS autopsy series. Because of its high prevalence and the discovery of population-specific variants of the virus, there is compelling evidence to suggest that JCV could be used to trace the path of human migrations. In addition, recent reports have shown that there are genotype-specific differences in the biological effects of JCV, e.g., JCV Type 2B occurs at a higher frequency in PML than is excreted in the urine of a control population. To date, the following work is in progress: (1) 210 urine samples have been collected from African- Americans to determine the genotype profile of JCV excreted in the urine of this group when compared to other ethnic groups, e.g., Caucasians, Hispanic-Americans and native Americans; (2) 115 urine samples have been collected from children and adolescents to identify patterns of urinary excretion of JCV in this population; (3) a retrospective study of 100 PML cases from 1970-1997 is being conducted in conjunction with the Department of Neuropathology at the AFIP; and (4) a pathological and molecular analysis of six PML cases occurring in African AIDS patients from East and West Africa has been studied and reported.